Respiratory failure is the leading cause of morbidity and mortality in people with acute and chronic cervical spinal cord injury (SCI). Thus, therapeutic approaches that restore respiratory function can significantly improve a person's quality of life. Our proposal is highly significant because: 1) we propose investigating a therapeutic strategy that may be more efficacious beyond the immediate post-injury period, 2) our pharmacological agents are already available to treat other clinical diseases, and 3) our proposal will utilize inherent mechanisms of spinal plasticity without the need for exogenous materials such as cellular or tissue transplantation. Our laboratory investigates functional plasticity of phrenic motoneurons, which innervate the primary inspiratory muscle in mammals - the diaphragm. Phrenic motor output is positively correlated to tidal volume;therefore, increasing phrenic motoneuron activity can improve tidal volume after SCI. Our approach uses small, highly permeable molecules (adenosine A2a receptor agonists) that mimic the effects of brain- derived neurotrophic factor (BDNF) on phrenic motoneuron activity (i.e., elicits a persistent increase in phrenic motor output). We recently demonstrated that cervical spinal administration of the A2a receptor agonist CGS 21680 strengthened spinal synaptic connections to phrenic motoneurons and elicited long-term increases in phrenic motor output below a cervical SCI. A2a-induced phrenic motor facilitation required TrkB receptor phosphorylation but did not require the TrkB ligand, BDNF. Thus, we propose that A2a receptor agonists transactivate TrkB receptors in vivo. The magnitude of A2a-induced phrenic motor facilitation increases with time post-injury, suggesting that A2a-induced phrenic motor recovery is particularly efficacious in the chronically injured population. Demonstrating clear translational potential, intraperitoneal injections of CGS 21680 also elicited long-lasting improvements in tidal volume in awake rats with cervical SCI. Thus, we propose that A2a receptor agonists represent a novel pharmacological approach to improve breathing in spinally injured rats. We will test our hypothesis that A2a receptor agonists elicit long-lasting improvements in tidal volume by using whole-body plethysmography. We will also investigate potential adverse and/or beneficial effects of these drugs on sensory and nonrespiratory motor systems affected by SCI. Strengths of this proposal include: 1) assessment of breathing in awake freely behaving spinally injured animals, 2) use of a clinically relevant injury model (i.e., C4 lateralized contusions) and 3) the availability of the Veterinary Clinical Investigations Center at the University of Pennsylvania to develop our pharmacological approach into future preclinical trials using dogs with naturally occurring SCI. The proposed experiments are highly significant because they may reveal a novel approach to improve respiratory motor function after chronic SCI. Additionally, this approach may be extrapolated to other motor deficits (i.e., locomotion and bladder control) that occur secondary to impaired motoneuron function in a variety of neurological disorders. Spinal cord injury causes life-threatening breathing difficulties because the nerves that control the respiratory muscles, the respiratory motoneurons, become less active. One approach to improve breathing after spinal cord injury is to restore respiratory motoneurons activity. To this end, we will investigate a promising new drug that persistently increases respiratory motoneuron activity, thereby improving breathing after spinal cord injury.